Melanocyte stem cells (McSCs) of the hair follicle can serve as a reservoir for melanocyte replenishment to the epidermal layer of the skin. This property has been demonstrated in patients with the depigmentation disease vitiligo, in which new pigmentation is found in a peri-follicular pattern surrounding hair follicles, following treatment with narrow-band ultraviolet B radiation (UVB). Unfortunately, repigmentation through UVB therapy is neither widespread nor durable. On the other hand, McSCs harboring mutations can serve as cells of origin for melanoma, the deadliest of skin cancers. Melanoma in this context can be initiated by the activation of McSCs in response to UVB exposure. It is our long-term goal to identify the molecular mechanisms through which UVB alters the activation and migration of McSCs to ultimately provide a significant impact leading to the improvement of vitiligo treatment and new methods of melanoma prevention. Our preliminary data indicate that a pro-inflammatory state in the skin, induced by UVB exposure, facilitates McSC translocation to the epidermis and melanoma initiation from mutant McSCs. We have also shown that loss of function in the architectural chromatin remodeling factor Hmga2 results in impairment of both McSC translocation and melanoma initiation through a cell extrinsic mechanism. The underlying molecular events through which inflammation and Hmga2 regulate these processes have not been identified. TNF signaling and neutrophil/macrophage recruitment have been determined as potential mediators of McSC proliferation and migration, and melanoma initiation from McSCs. It is the central hypothesis of this proposal that UVB-mediated McSC translocation, and melanoma initiation from McSCs, requires inflammatory cell influx and TNF signaling, which is induced by tissue-specific Hmga2 transcriptional regulation. In this proposal, we will test whether specific cell populations and signaling pathways are responsible for UVB-mediated McSC translocation and melanoma initiation via Aim 1) directed at the necessity of inflammation mediated recruitment of neutrophils and macrophages, Aim 2) directed at the necessity and sufficiency of cytokine signaling mediated by Tnf?, and Aim 3) directed at defining the cell population and downstream transcription changes dependent upon Hmga2. Our approach will utilize our innovative model system to define these processes in vivo, using deletion/overexpression by cell specific genetic manipulation, antibody and small molecule neutralization of cell populations and signaling pathways, and transcriptomic profiling on isolated cell populations. Understanding and conclusively defining the cell populations and transcriptomic changes occurring during UVB-mediated McSC translocation and melanoma initiation will lead to testing of novel strategies for vitiligo treatment and melanoma prevention. These goals are directly in line with the mission at NIAMS to improve the health of patients suffering from skin diseases.